1. What is the definition of minor and major protocol violation according to GCP or other legislation reference?

There is no definition, within both GCP and the UK legislation, of the terms major or minor protocol violation and therefore the terms do not have a specific reference in law. There are a number of generalised definitions that are currently in use within the industry which you will undoubtedly find by an internet search, but as these are neither referenced in the UK legislation nor in GCP we cannot comment on their usage.

A deviation is an unplanned departure from the protocol directions. Intended departures should be formally managed via substantial and non-substantial amendments (see the question below).

If deviations from the protocol take place during the trial, the deviation must be fully documented and the information provided to the relevant parties for onward consideration and reference in the clinical study report, and/or publication(s). The relevant parties include (but may not be limited to) data management, medical writing and quality assurance.

The deviation documentation should consider the impact of the deviation on both the safety of the trial subjects and the integrity of the data (or further trial conduct).

There are two types of change: substantial and non-substantial amendments.

In UK SI 2004:1031 a substantial amendment is defined as an amendment to the authorisation which is likely to affect to a significant degree:
a) the safety or physical or mental integrity of the subjects in the trial
b) the scientific value of the trial
c) the conduct or management of the trial
d) the quality or safety of any investigational medicinal product used in the trial.

All substantial amendments to a protocol must be submitted to the Competent Authority and/or (depending on the nature of the amendment) the research ethics committee (REC) for approval prior to implementation of that change. Unless of course the change is an urgent safety measure, in which case the change can be put in place immediately for the safety of the patients, but the MHRA must be notified of this urgent safety measure within three days of it occurring.

Non-substantial amendments to protocols do not need to be submitted to the MHRA or the REC but the legislation requires that a record of the non-substantial amendment is retained and that the Licensing Authority may request these records.